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Hematopoiesis
Setd2 regulates quiescence and differentiation of adult hematopoietic stem cells by restricting RNA polymerase II elongation
Haematologica 2018 Volume 103(7):1110-1123
1Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 2Division of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, OH, USA; 3Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, China; 4Division of Immunobiology and Center for Systems Immunology,Cincinnati Children’s Hospital Medical Center, OH, USA; and 5State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital and Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Yile Zhou,1,2 Xiaomei Yan,2 Xiaomin Feng,2 Jiachen Bu,2,3 Yunzhu Dong,2 Peipei Lin,2 Yoshihiro Hayashi,2 Rui Huang,2 Andre Olsson,4
Paul R. Andreassen,2 H. Leighton Grimes,4 Qian-fei Wang,3
Tao Cheng,5 Zhijian Xiao,5 Jie Jin1,* and Gang Huang2,*
*JJ and GH contributed equally to this study as joint senior authors
ABSTRACT
SET domain containing 2 (Setd2), encoding a histone methyltrans- ferase, is associated with many hematopoietic diseases when mutated. By generating a novel exon 6 conditional knockout mouse model, we describe an essential role of Setd2 in maintaining the adult hematopoietic stem cells. Loss of Setd2 results in leukopenia, anemia, and increased platelets accompanied by hypocellularity, ery- throid dysplasia, and mild fibrosis in bone marrow. Setd2 knockout mice show significantly decreased hematopoietic stem and progenitor cells except for erythroid progenitors. Setd2 knockout hematopoietic stem cells fail to establish long-term bone marrow reconstitution after transplantation because of the loss of quiescence, increased apoptosis, and reduced multiple-lineage terminal differentiation potential. Bioinformatic analysis revealed that the hematopoietic stem cells exit from quiescence and commit to differentiation, which lead to hematopoietic stem cell exhaustion. Mechanistically, we attribute an important Setd2 function in murine adult hematopoietic stem cells to the inhibition of the Nsd1/2/3 transcriptional complex, which recruits super elongation complex and controls RNA polymerase II elongation on a subset of target genes, including Myc. Our results reveal a critical role of Setd2 in regulating quiescence and differentiation of hematopoi- etic stem cells through restricting the NSDs/SEC mediated RNA poly- merase II elongation.
Introduction
Hematopoietic stem cells (HSCs) are characterized by their capability for self- renewal and multi-potency.1,2 Hematopoiesis is dynamically controlled by the interplay of transcriptional and epigenetic networks, while dysregulation of these networks can lead to unfitness of hematopoiesis, cellular transformation, and hematologic diseases. Multiple drugs targeting epigenetic modulators have shown promising effects on certain hematopoietic diseases.3,4 Thus, a better understanding of how the epigenome is regulated in hematopoiesis may provide insights that can improve the treatment of hematologic disorders.
Correspondence:
gang.huang@cchmc.org or jiej0503@zju.edu.cn
Received: Juanary 3, 2018. Accepted: April 6, 2018. Pre-published: April 12, 2018.
doi:10.3324/haematol.2018.187708
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/7/1110
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